Penn Researchers Discover Initial
Steps in the Development of TasteWnt Protein Required for Taste Buds and Wiring of Taste Signals
to the Brain

(PHILADELPHIA) - Of the five senses, taste is one of the least understood,
but now researchers at the University of Pennsylvania School of
Medicine have come one step closer to understanding how the sense
of taste develops. They have pinpointed a molecular pathway that regulates
the development of taste buds. Using genetically engineered mice, they
discovered that a signaling pathway activated by small proteins called
Wnts is required for initiating taste-bud formation. They have also determined
that Wnt proteins are required for hooking up the wiring of taste signals
to the brain.

Senior author Sarah E. Millar, PhD, Associate Professor
in the Departments of Dermatology and Cell and Developmental Biology,
Penn postdoctoral fellow Fei Liu, PhD, and colleagues
report their findings in the most recent online issue of Nature Genetics.
“The developmental biology of taste is underexplored,” says
Millar of her team’s impetus for the study.

The researchers demonstrated that blocking the action of Wnt proteins
in surface cells of the developing tongue prevents taste-bud formation,
while stimulating Wnt activity causes the formation of excessive numbers
of enlarged taste papillae that are able to attract taste-related nerve
fibers. This study represents the first genetic analysis of taste-organ
initiation in mammals. While these studies were performed in mice, the
researchers believe that their findings will also hold true for understanding
the basis of taste-bud development in humans.

Taste buds are the sensory organs that transmit chemical stimuli from
food and other sources to nerve cells, which convey these signals to the
taste centers in the brain. Taste buds sit in the small bumps in the surface
and sides of the tongue called papillae.

The signaling pathway activated by Wnt proteins is critical to the development
of many organ systems, and its inappropriate activation causes human diseases
including colon cancer. In previous studies, Millar and colleagues have
shown that this pathway is essential for initiating the formation of hair
follicles and mammary glands in mice.

The sites of Wnt signaling are easily visualized in specially engineered
transgenic mice, using an enzymatic assay. “We noticed in the tongue
that there was this beautiful pattern of blue spots that correspond to
the developing taste papillae,” says Millar. “This connected
the Wnt pathway to their development.”

In the present study, the researchers found that in mice in which the
actions of Wnt proteins were blocked, taste papilla buds completely failed
to develop. Conversely, in mice in which Wnt signaling was over activated,
their tongues were covered with many and large papillae and taste buds.

“Unlike most surface epithelial cells, taste buds have characteristics
of neurons as well as skin. Like other types of epithelial cells they
turn over and regenerate, but they also express chemoreceptors and make
synapses with neurons,” explains Millar. The group studied how developing
taste buds become wired into the nervous system. In early tongue development,
neurons enter the tongue epithelium and make synapses with taste bud cells.
This study confirmed that taste buds produce signals that attract nerve
fibers to them. When taste-bud development was prevented by blocking Wnt
signaling, the nerve fibers did not enter the tongue epithelium.

“They don’t know where to go on their own,” she says.

Millar also mentions that by now understanding the basis for the initiation
of taste-papilla formation, the evolution and difference between species
in the numbers and patterns of taste buds can be more fully explored.
All animals that taste have taste buds, but there are differences, for
example humans have more (around 200) taste papillae than mice, and they
are arranged in a different pattern.

Future research directions will include determining whether Wnt signaling
is also important for the periodic regeneration of taste buds from taste-bud
stem cells that occurs throughout life in adult animals. Taste-bud regeneration
can be affected by chemotherapy, so understanding this process will have
important implications for patient care.

The research was supported by the National Institutes of Health. In addition
to Millar and Liu, co-authors on the paper are: Natalie Gallant, Seshamma
T. Reddy, and Thomas Andl, from Penn; Shoba Thirumangalathu and Linda
Barlow from the University of Colorado Health Sciences Center; Steven
Yang and Andrzej A. Dlugosz from the University of Michigan; Cristi L.
Stoick-Cooper and Randall T. Moon from the Howard Hughes Medical Institute
and University of Washington; and Makoto M. Taketo from Kyoto University.

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